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Incomplete 483 Responses Lead to Warning Letter

Key GMP learning opportunities explored

Incomplete 483 Responses Lead to Warning Letter

We can learn a lot from warning letters.

This manufacturer was inspected in April 2022, where they received some 483s. The company subsequently responded to some 483s, but according to the warning letter, “Not all of the items on the issued Form 483 were addressed in your response.” In my experience, most 483s can be addressed before they become warning letters.

I talk about improper 483 responses here.

Here is an example from the warning letter.
From warning letter. “We have reviewed your June 23, 2022 response to the form FDA 483. We are unable to evaluate the adequacy of your response because you did not provide documentation demonstrating you have established specifications… You provide documents you describe as revised finished product specifications for the … product. We note that these documents do not demonstrate that you have established specifications that provide standards to confirm the identity, purity, strength, and composition of the finished batch of your dietary supplements. For example, the finished product specification for … product lists an “identification” specification of “Conforms to Standard” with a test method of “Eurofins or eq.” and a frequency of “Rotational.” “Conforms to standard” does not specify the extent to which the component must conform. “Eurofins or eq.” is not a test method, and “Rotational” does not describe the frequency of when testing is to occur.

Let’s break this down.

🔹Identification: The company lists the type of identification as “conforms to standard” but does not provide information on what that standard is. The company is close but, unfortunately, falls short of GMP requirements. Here is howI think about GMP documents, such as this specification sheet. Will someone unfamiliar with your process be able to step in and understand how to test the product if there is no “institutional knowledge?” It is the "recipe" for staff to follow.
🔹Test method: The company lists “Eurofins or eq” which is the name of the laboratory, not the name of the method, such as “AOAC 121804.”
🔹Frequency of testing is listed as “Rotational,” which is not sufficient. It should state “Test all” or refer to an SOP on skip lot testing.

Incorrect reference samples are also cited.

👉From warning letter. "You failed to establish and follow laboratory control processes that are reviewed and approved by quality control personnel to use criteria for selecting standard reference materials used in performing tests and examinations… Specifically, the FTIR analysis performed by your third-party laboratory uses previous shipments of components as the reference for testing and they do not own a reference library for the FTIR tests. Testing components against previous shipments of the component may confirm receipt of the same component but this does not ensure the identity, purity, quality, and strength of the component is thoroughly characterized.”

I admit this is how I tested identity around 2010 until I realized that having a qualified reference sample was essential. In this example, the third-party lab should have handled this rather than just depending on previously provided reference samples, and the quality personnel should not have allowed this.

One more learning opportunity.
🔹Theoretical yield calculation helps “error-proof” manufacturing. Let’s use the example of a capsule product. First, the powder needs to be blended. If the theoretical yield is off, this will signify too much or too little of an ingredient was added and, therefore, should not “pass” to the encapsulation process.

🔹The same Is true for encapsulation. If a company has substantially more capsules than the theoretical yield, this signifies the capsules are underweight and not at label claim. The production should be stopped for evaluation here.

🔹If the yield is too high in bottling, this shows there are likely not enough capsules in each bottle. This lily-pad approach to quality is designed to stop problems before they happen.
From warning letter: "A statement of the theoretical yield of a manufactured dietary supplement expected at each point, step, or stage of the manufacturing process and the maximum and minimum percentages of theoretical yield beyond which a deviation investigation of a batch is necessary."

Interested in learning more about GMPs? Here are a few webinars you may enjoy.
🔹Distributor requirements for supplements.
🔹Getting ready for FDA inspections

There are so many learning lessons. Read the full letter here. 

Disclaimer: The educational information provided here is for informational purposes only. Contact an attorney for specific legal advice. Rule #1 in compliance is to ensure marketing is truthful and not misleading.

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